Project Summary Acute kidney injury (AKI) is common and increases mortality. AKI complicates up to 20% of hospital admissions and 30 to 50% of ICU admissions. Sepsis occurs in 40-45% of patients after AKI diagnosis and doubles mortality. In fact, sepsis is the leading cause of death in patients with AKI. Immunoparalysis is a complication of sepsis and other insults (e.g., cardiac surgery) that is known to be associated with increased risk of subsequent infection, sepsis, and mortality. In this grant, we propose that AKI is a specific cause of immunoparalysis, thus explaining the known association between AKI and subsequent sepsis. Based on preliminary data, we propose that patients with and without AKI after cardiopulmonary bypass surgery (CPB) are the ideal population to determine if AKI is a risk factor for immunoparalysis. Our overall hypothesis is that AKI is a risk factor for immunoparalysis. In Aim 1 we propose to determine if patients with AKI have a higher rate of immunoparalysis after CPB. Immunoparalysis will be assessed using methods: 1) TNF levels after ex vivo endotoxin stimulation of whole blood, and 2) blood monocyte HLA-DR (mHLA-DR) levels by flow cytometry. Both of these methods are sufficiently valid and robust enough that they are being utilized to identify immunoparalysis for clinical trial enrollment of immune stimulating agents in conditions such as trauma and sepsis. In Aim 2 we propose to determine if the severity of immunoparalysis is greater among patients with AKI after CPB compared to patients without AKI. In Aim 3 we propose to determine if the presence of AKI in combination with ex vivo endotoxin stimulation and mHLA-DR can improve risk stratification for the development of subsequent infection versus ex vivo endotoxin stimulation or mHLA-DR alone. If the aims of this grant are achieved, immunoparalysis will be established as a novel complication of AKI and potential mediators will be identified. Since immunoparalysis is associated with sepsis, and sepsis after AKI doubles mortality, this proposal will lay the groundwork for an interventional clinical trial in AKI that may ultimately reduce mortality; this is especially true since agents to reverse immunoparalysis are currently available, are associated with improved outcomes, and are being utilized in clinical studies.